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Over the last few decades, there has been a recurring trend in cardiac nutritional science. Observational data shows a strong association between a nutritional deficiency and worse cardiovascular (CVD) outcomes, generating a hype for supplementation. This is followed by small intervention trials of nutritional supplementation that yield mixed results, with meta-analyses unable to provide clarity due to heterogeneity in study designs. Meanwhile, the buzz catches on with health care practitioners and the lay public alike because who doesn't like the simple idea of taking a natural supplement to improve heart health? Finally, large-scale randomized controlled trials (RCTs) are undertaken and fail to show any benefit (vitamin C and E, beta-carotene, folic acid to reduce homocysteine, and, most recently, omega-3 fatty acids), and in some cases even show harm (vitamin E).

The evidence for an association between vitamin D and CVD is robust. The prevalence of vitamin D deficiency increases with distance from the equator, and Northern European countries have the highest deficiency rates. In a similar fashion, rates of diabetes, hypertension, and CVD increase with the distance from the equator. Epidemiologic studies show a strong association between vitamin D deficiency and not only CVD risk factors (hypertension, diabetes, metabolic syndrome, left ventricular hypertrophy), but also myocardial infarction, and cardiovascular and all-cause mortality.^1-5 However, it is well known that association does not equal causation. True biological causality requires consistency of association, strength of association, dose response, temporality, and biological plausibility. So does the availabe data imply causality of vitamin D deficiency for CVD?

Vitamin D is obtained from dietary sources, like fatty fish or fortified foods, or through the conversion of 7-dehydro cholesterol in the skin from exposure to UVB radiation. It is then hydroxylated by the liver to 25-hydroxy vitamin D (25-OH D). This is still inactive, but its level correlates well with the overall vitamin D status. It is then further hydroxylated in the kidneys to its active form, 1,25-dihydroxyvitamin D (or calcitriol). Calcitriol regulates calcium metabolism by enhancing intestinal calcium absorption and mobilizing calcium from the skeleton.

Although there is no consensus on the optimal blood level of 25-OH D, most experts believe that a level below 20-30 ng/ml signifies deficiency. Using this cutoff, the prevalence of deficiency is estimated at 50-60% among U.S. adults; worldwide, it affects up to 1 billion people.¹ Darker-skinned ethnic groups require considerably more sun exposure to synthesize adequate amounts of vitamin D compared with Caucasians. Other risk factors for vitamin D deficiency include sun avoidance strategies like sunscreen, sedentary indoor lifestyle, obesity, renal and hepatic dysfunction, older age, and institutionalization. A report from the Institute of Medicine (IOM) recommends a daily intake of 600 IU for adults, with older adults (>70 years) needing 800 IU, and a safe upper intake level of 4000 IU.⁶ Each additional 100 IU of vitamin D taken daily increases 25(OH) D levels by about 1 ng/ml.

Many cell types, including vascular smooth muscle cells, endothelial cells, and cardiomyocytes, produce 1α-hydroxylase, which converts 25-OH D to calcitriol. Vitamin D deficiency leads to upregulation of the renin-angiotensin-aldosterone system. Small intervention trials of vitamin D supplementation have shown significant reduction in blood pressure,⁷ though meta-analyses have reported conflicting results.⁸ Vitamin D deficiency leads to pancreatic beta-cell dysfunction and insulin resistance. Although there is strong observational data connecting vitamin D deficiency with incident diabetes, trials of supplementation have yielded mixed results.⁸ Vitamin D deficiency also leads to increased parathyroid hormone (PTH) levels, which in turn can lead to left ventricular and vascular smooth muscle hypertrophy.

Data from the Offspring Cohort of the Framingham Heart Study show an inverse relationship between vitamin D levels and incident CVD.⁹ A report from the National Health and Nutrition Examination Survey III (NHANES III) showed an inverse relation with all-cause mortality but not cardiovascular mortality.¹⁰ Both of these studies also point to a U-shaped relationship between vitamin D levels and cardiovascular mortality, with high levels (>50 ng/ml) associated with a slightly increased mortality. A novel method to overcome the limitations inherent in observational data is the Mendelian randomization approach, in which causality is inferred from associations between genetic variants that mimic the influence of a modifiable risk factor and the clinical outcome of interest. This approach largely circumvents confounding and reverse causation, but is still limited by pleiotropic effects of genetic variants. Mendelian randomization studies of large cohorts showed no causal link between genetic variants causing low 25-OH D and obesity,¹¹ and possible causal links with hypertension¹² and diabetes.¹³ Mimicking the observational data, vitamin D deficiency was linked with all-cause mortality, but not cardiovascular mortality.¹⁴

In a meta-analysis of 18 RCTs of over 57,000 participants, the summary relative risk for all-cause mortality was reduced by 7% with vitamin D therapy.¹⁵ Another meta-analysis of eight RCTs showed a statistically non-significant reduction in CVD risk.¹⁶ The included trials had considerable heterogeneity in study design and vitamin D dose used for supplementation. None had CVD as a pre-specified primary outcome.¹⁷ A British RCT of 2,700 elderly participants who received either vitamin D 100,000 IU or placebo every four months for five years found no statistically significant difference in various CVD outcomes.¹⁸ A systematic review done by the Agency for Healthcare Research and Quality in 2009 found the overall evidence for vitamin D supplementation and improved CVD outcomes as inconclusive.¹⁹

There are two National Institutes of Health (NIH)-funded RCTs with CVD as a primary outcome that will hopefully provide some clarity. The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing double-blind, placebo-controlled RCT to assess the impact of 2,000 IU vitamin D and/or omega-3 fatty acids on heart disease, stroke, and cancer in 20,000 healthy men and women in the U.S.¹⁷ Enrollment for VITAL is complete, and results are expected in 2017. Another RCT (Vitamin D, Insulin Resistance, and Cardiovascular Disease, NCT00736632) is currently enrolling patients with coexistent diabetes, hypertension, and vitamin D deficiency.

Despite the widespread prevalence of vitamin D deficiency, the strong and consistent association with CVD risk factors and mortality, as well as biological plausibility from mechanistic laboratory studies, it is still unclear whether vitamin D is just a marker for increased CVD risk or actually plays a role in the pathogenesis of CVD. Potential confounders to the observational data include obesity, physical activity, sun exposure, and nutritional status. Small interventional trials done so far have not given a convincing answer, so we are eagerly awaiting the results of ongoing RCTs. For now, as the IOM report recommends, treat vitamin D deficiency for bone health, but not heart health.

References

1. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81.
2. Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR. Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone 2002;30:77-7.
3. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med 2008;168:1174-80.
4. Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med 2008;168:1340-9.
5. Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2007;167:1159-65.
6. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Washington, D.C: National Academies Press; 2011.
7. Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet 1998;352:709-10.
8. Pittas AG, Chung M, Trikalinos T, et al. Systemic review: vitamin D and cardiometabolic outcomes. Ann Intern Med 2010;152:307-14.
9. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008;117:503-11.
10. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008;168:1629–37.
11. Vimaleswaran KS, Berry DJ, Lu C, et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med 2013;10:e1001383.
12. Vimaleswaran KS, Cavadino A, Berry DJ, et al. Association of vitamin D status with arterial blood pressure and hypertension risk: A Mendelian randomisation study. Lancet Diabetes Endocrinol 2014;2:719-29.
13. Afzal S, Brøndum-Jacobsen P, Bojesen SE, Nordestgaard BG. Vitamin D concentration, obesity, and risk of diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol 2014;2:298-306.
14. Afzal S1, Brøndum-Jacobsen P, Bojesen SE, Nordestgaard BG. Genetically low vitamin D concentrations and increased mortality: mendelian randomisation analysis in three large cohorts. BMJ 2014;349:g6330.
15. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007;167:1730-7.
16. Wang L, Manson JE, Song Y, Sesso H. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 2010;152:315-23.
17. Shapses SA, Manson JE. Vitamin D and prevention of cardiovascular disease and diabetes: why the evidence falls short. JAMA 2011;305:2565-6.
18. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326:469.
19. Chung M, Balk EM, Brendel M, et al. Vitamin D and calcium: systematic review of Health Outcomes. Evidence Report/Technology Assessment No. 183. AHRQ Publication No. 09-E015, Rockville, MD: Agency for Healthcare Research and Quality; 2009.

Keywords: 25-Hydroxyvitamin D 2, Ascorbic Acid, Calcitriol, Cholesterol, Fatty Acids, Homocysteine, Hypertension, Insulin Resistance, Life Style, Metabolic Syndrome, Obesity, Secondary Prevention, Vitamins, Aged, Ascorbic Acid, Blood Pressure, Calcium, Cholesterol, Consensus, Diabetes Mellitus, Double-Blind Method, Endothelial Cells, Epidemiologic Studies, Ethnic Groups, Fatty Acids, Omega-3, Folic Acid, Health Services Research, Hypertrophy, Hypertrophy, Left Ventricular, Institutionalization, Liver, Mixed Function Oxygenases, Motor Activity, Myocardial Infarction, Myocytes, Smooth Muscle, Neoplasms, Nutrition Surveys, Nutritional Sciences, Nutritional Status, Parathyroid Hormone, Prevalence, Random Allocation, Renin-Angiotensin System, Risk, Risk Factors, Stroke, Up-Regulation, Risk Factors, Vitamin D, Vitamin D Deficiency, Vitamin E, Vitamin D Deficiency, beta Carotene

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